Abstract The environmental obesogen hypothesis posits that lipophilic persistent organic pollutants (POPs) accumulate in adipose tissue (AT) and can disrupt metabolic systems. However, the underlying molecular mechanisms of these toxicants on AT function remain poorly understood. As the most studied POP, dichlorodiphenyl- dichloroethylene (DDE), a persistent metabolite of the insecticide dichlorodiphenyl-trichloroethane (DDT), provides a model for assessing the metabolic health impact of lipophilic POPs. Almost all U.S. children and adolescents have detectable DDE blood levels. Despite abundant evidence from experimental studies showing that DDE disrupts metabolic homeostasis, mechanisms underlying metabolic disruption by DDE in humans are unclear. We therefore propose a novel study design for investigating mechanisms of DDE metabolic effects in humans, based on a remarkable archive of clinical data and visceral AT samples from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study and an in vitro human adipocyte experimental model. We hypothesize that the large metabolic changes after bariatric surgery provide a ?natural experiment? that will magnify effects of the prototypical obesogen DDE, and that DDE in visceral AT will attenuate the reduction in body mass index and insulin resistance after bariatric surgery in a concentration-dependent manner (Aim 1). Although we know that high doses of DDE impair thermogenesis and insulin signaling in animal models, we still do not know whether these mechanisms underlie metabolic disruption by DDE in humans. We will assess effects of DDE on these pathways in a human primary adipocyte cell line, an experimental model that will be free from the potential for uncontrolled confounding in human observational studies and that may also identify new pathways (Aim 2). We will then test these pathways in metabolome and transcriptome profiles of human AT from Teen-LABS study participants, using a hierarchical modeling approach (Aim 3). Finally, we will integrate results from the DDE omics analyses in human AT and in the adipocyte cell line, using a novel latent variable modeling framework, to identify subgroups of adolescents who have less weight loss and less improvement in insulin resistance after bariatric surgery, based on their DDE exposure and multi-omics profile in AT (Aim 4). The proposed research will be the first human study to examine mechanisms of DDE toxicity to AT in humans, using adipose tissue-specific exposure and omic measures, and clinically relevant metabolic outcomes such as BMI and insulin resistance. A strong interdisciplinary team of investigators brings expertise in environmental epidemiology, bariatric surgery, toxicology, omics, and biostatistics. Our study, integrating in vitro and human observational approaches, has the potential to establish a new paradigm for the study of lipophilic obesogenic chemicals and to advance our understanding of environmental contributions to obesity and type 2 diabetes.